Mortality and morbidity caused by the pulmonary pathogen Mycobacterium tuberculosis (Mtb) remains alarmingly high. Elucidating the mechanisms that curtail host Th1 immunity is not only important for understanding immunopathology in TB, but is also necessary to gain a better appreciation for how virulent Mtb usurp these regulatory checks and balances in the host for their own survival. The focus of this application is to examine the immunosuppressive pathways activated in the host by TLR2 signaling in DCs that control Th1 effector and memory responses. Several complementary regulatory circuits may be activated that together modulate host immunity such that protection is achieved with minimal damage to the host. In studies examining Mtb interaction with murine bone marrow-derived macrophages and DCs, it was observed that in response to Mtb infection, DCs released abundant Interleukin (IL)-12, while secretion was limited in macrophages. Furthermore, Mtb-induced remodeling at the p40 promoter and IL-12 release in DCs was Toll-like receptor (TLR) 9-dependent, and in contrast TLR2 dependent in macrophages. The release of the immunosuppressive/anti-inflammatory cytokine IL-10, however, was predominantly TLR2-dependent in both cell types. Collectively, these findings demonstrate that, unlike macrophages, DCs are able to engage the more efficient TLR9 pathway for IL-12 gene induction, while using the TLR2 pathway for induction of IL-10. What is the evolutionary advantage to the host of the differential TLR usage by DCs for IL-12 and IL-10 production? It is hypothesized that the segregation of TLR usage by DCs is a means to coordinate and regulate the expression of two opposing cytokines such that the host can achieve a balance between protection and pathology. The hypothesis will be tested in the following two aims: Aim1. Innate IL-10 released in response to Mtb and TLR2 interaction promotes "alternative activation" of DCs and dampens their Th1 activation potential. Aim2. Innate IL-10 released in response to Mtb and TLR2 interaction promotes "regulatory DCs" that activate T regulatory cells to control the magnitude of Th1 activation. The long-term goal is to gain a better insight into how Th1 immunity is regulated in the host. Eight million new cases of tuberculosis occur each year, accounting for approximately 7% of all deaths and 26% of all avoidable adult deaths in developing countries. TB truly constitutes a global health emergency. Data generated from this proposal will provide new strategies for making better vaccines against Tuberculosis. [unreadable] [unreadable] [unreadable]